This proposal details a comprehensive 5-year program for Dr. Paul J Planet's career development in basic research in Infectious Diseases. Dr. Planet has designed his mentored research program to provide both additional scientific training and skills that will allow him to succeed as an independent investigator and physician-scientist. Dr. Planet's scientific training objective is to add to his background in molecular microbiology and phylogenetics by gaining experience in the areas of host-pathogen immunology, epidemiology, and microbiome studies. His career objective is to successfully make the transition to being an independent investigator. Alice Prince M.D. will be Dr. Planet's primary mentor for scientific and career development. Dr. Prince is a leader in the fields of host-pathogen interactions, innate immunity, and infectious diseases. Dr. Planet has established an advisory committee that will guide his scientific progress and career development that is composed of microbiologists (Dr. Noah Fierer, Dr. Franklin Lowy, Dr. Barry Kreiswirth) with expertise in microbial ecology, immunology, epidemiology, genomics, animal models, and pathogenesis. He will also utilize the considerable resources for career development and scientific collaboration at Columbia University. Dr. Planet's project focuses on the remarkable ability of Staphylococcus aureus to colonize and persist on human skin and mucosal tissues. Colonization by S. aureus is critical for the spread of disease, and it is a major risk factor for infection. The central hypothesis is that Staphylococcus aureus improves its ability to colonize by triggering the host's innate immune response to preferentially eliminate other commensal bacterial competitors. In a mouse model, Dr. Planet recently found that the ability of S. aureus to manipulate the host's immune response is due, in part, to production of Protein A (SpA). He has also shown that the variable tandem repeat region (Xr) of SpA appears to be critical for this effect. Preliminary data suggests that SpA may act by increasing expression of antimicrobial peptides produced by the host epithelium. The specific aims of the proposal are to: (1) Test the hypothesis that the Xr region of SpA affects colonization of resident flora in a mouse model, and delineate the specific ecological shifts that occur. (2) Determine the primary elements of the human innate immune response that are triggered by Xr leading to clearance of other flora. PUBLIC HEALTH RELEVANCE: Staphylococcus aureus is a common and aggressive human pathogen that first colonizes patients prior to causing infection. Almost 30% of healthy people carry S. aureus on their skin and mucous membranes. This proposal will identify the mechanisms that enable S. aureus to so effectively outcompete other microorganisms on human tissues.